Amelioration of mitochondrial function by a novel antioxidant U-101033E following traumatic brain injury in rats.
In the present study, a severe traumatic brain injury (TBI) was produced over the right parietal cortex of rats using the controlled cortical impact injury (CCII) model. TBI perturbed calcium homeostasis and impaired electron transfer and energy coupling activities of forebrain mitochondria isolated from injured hemispheres with a maximal injury at 12-72 h. Efficacy of the blood-brain barrier penetrating antioxidant U-101033E on TBI-induced mitochondrial impairment was evaluated. In the dose-response experiment, two i.v. boluses (vehicle or 1-10 mg/kg of U-101033E) were administered at 5 min and 2h post-TBI. Forebrain mitochondria from each hemisphere were examined at 12 h post-injury. With respect to forebrain mitochondrial dysfunction, the drug showed a bell-shaped dose-response curve with an optimal dose of 3 mg/kg (n = 5, p < 0.05 vs. vehicle). In the time-course experiment, two i.v. boluses of 3 mg U-101033E/kg (the optimal dose) were given at 5 min and 2 h post-injury and forebrain mitochondria were examined at 6 h-14 days post-injury. U-101033E significantly restored electron transfer, energy coupling capacity, and Ca2+ transport capacity during 6 h to 14 days post-injury. Our data indicate that the antioxidant U-101033E administered post-injury at proper dosage can effectively restore TBI-induced mitochondrial dysfunction and support the contention that oxidative stress plays an important role in the pathogenesis of TBI.
Xiong
Y
Y
Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Peterson
P L
PL
Muizelaar
J P
JP
Lee
C P
CP
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001930:Brain Injuries / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015431:Weight Loss / Q000187:drug effects
D000975:Antioxidants; D018696:Neuroprotective Agents; D011743:Pyrimidines; D011759:Pyrrolidines; C101923:U 101033E; D002118:Calcium